Conventional methods of forming a cyclodextrin complex or inclusion compound of a drug slightly soluble in water include the method in which a saturated aqueous solution of the drug and cyclodextrin is cooled to precipitate the complex, the method in which an aqueous solution of the drug and cyclodextrin is lyophilized [M. Kurozumi et al., Chemical and Pharmaceutical Bulletin, 23, 1421 (1975)], and the mixed milling method [Y. Nakai et al., Chemical and Pharmaceutical Bulletin, 26, 2419 (1978)]. However, the solubility of the complex of a slightly water-soluble drug and cyclodextrin as obtained by these methods is not sufficient to permit its use as an injection. Also, drug stability is lessened in some cases.
Further, Japanese published unexamined patent application No. 63-135402 mentions the pharmaceutical composition which comprises maltosyl-.beta.-cyclodextrin and at least one compound selected from the group consisting of digitonin, nifedipine, flurubiprofen, isosorbide nitrate, phenytoin, progesterone and testosterone. However, the reference is silent about a fumagillol derivative.
There is demand for the development of a complex usable as a preparation for injection and of a method of industrial production thereof by increasing the solubility and stability of the fumagillol derivative, a drug which is only slightly soluble in water.
In view of this situation, the present inventors investigated increasing the water solubility of a fumagillol derivative (or a salt thereof), which is slightly soluble in water, and found that a liquid complex with markedly improved solubility of a fumagillol derivative can be obtained by suspending the fumagillol derivative in an aqueous solution containing highly water-soluble cyclodextrin derivative at about 100 mg/ml or more, stirring the suspension to obtain a solution, and filtering the solution to remove the undissolved fumagillol derivative upon completion of the progress of dissolution, and that a powdered complex with markedly improved water solubility of the fumagillol derivative can be obtained by drying the liquid. The inventors made further investigations based on this finding, and developed the present invention.